Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action

Autor:	Euphemia Leung, Peter J. Choi, Thomas I. H. Park, William A. Denny, Jiney Jose, Jóhannes Reynisson, Petr Tomek, Moana Tercel, Elizabeth Cooper
Rok vydání:	2022
Předmět:	RM Indoles Pyridines MHI-148 medicine.medical_treatment Pharmaceutical Science Antineoplastic Agents Breast Neoplasms CHO Cells Palbociclib Piperazines Analytical Chemistry RC0254 breast cancer QD241-441 Breast cancer Cricetulus RA0421 Drug Discovery medicine Cytotoxic T cell Animals Humans RM695 Physical and Theoretical Chemistry Chemotherapy Chemistry Cytotoxins Organic Chemistry R735 CDK4/6 inhibitor palbociclib near-infrared fluorescent (NIRF) cell cycle arrest Carbocyanines medicine.disease Metastatic breast cancer HEK293 Cells Mechanism of action Chemistry (miscellaneous) Cancer research Molecular Medicine Female medicine.symptom G1 phase Conjugate
Zdroj:	Molecules; Volume 27; Issue 3; Pages: 880 Molecules, Vol 27, Iss 880, p 880 (2022)
ISSN:	1420-3049
DOI:	10.3390/molecules27030880
Popis:	The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative as well as estrogen receptor positive breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells suggesting the mechanism of action differed from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.
Databáze:	OpenAIRE
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